CN106554303A - Thienopyridine analog derivative and its production and use - Google Patents
Thienopyridine analog derivative and its production and use Download PDFInfo
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- CN106554303A CN106554303A CN201510621912.5A CN201510621912A CN106554303A CN 106554303 A CN106554303 A CN 106554303A CN 201510621912 A CN201510621912 A CN 201510621912A CN 106554303 A CN106554303 A CN 106554303A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
Abstract
The present invention relates to a kind of thienopyridine analog derivative and its production and use, thienopyridine analog derivative of the present invention has the structure shown in lower formula (I), wherein R1、R2、R3It is as defined in the claims with m, present invention additionally comprises the preparation method of formula (I) compound, its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture, pharmaceutical composition containing them and its purposes as medicine, the postoperative thrombosiss particularly for preventing or treating atheromatosiss, myocardial infarction, apoplexy, ischemic cerebral thrombosiss, peripheral arterial disease, acute coronary syndrome or calcification score.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to optically active thienopyridine derivative and preparation method thereof and the purposes in pharmacy, more particularly to thienopyridine derivative is preparing prevention or is treating thrombosis and the purposes in thromboembolism relevant disease medicine.
Background technology
Thrombus disease is that the lumen of vessels caused by thrombosis is narrow and inaccessible and cause main organs ischemia and infraction to occur and causes the various diseases of malfunction.Adhesion and aggregation, stasis of blood stream, the activation of thrombin that thrombotic factor has platelet on injured blood vessel wall surface is caused to promote the formation of thrombin and fibrinolytic low.The medicine for being clinically used for thrombus treatment can be divided into 3 classes：Antiplatelet drug, anticoagulant and Thrombolytic Drugs.Antiplatelet drug has the effect for the treatment of and prevention concurrently, is the main category in antithrombotic reagent.Antiplatelet drug refers to that can suppress hematoblastic sticks, assembles and release function, prevents the formation of thrombosis, for preventing and treating the medicine of ischemic cardiovascular and cerebral vascular disease, periphery thrombotic disease.Antiplatelet drug is divided into into three generations at present：Aspirin is the first generation, thiophene chloropyridine is the second filial generation (thiophene pyridines, a class antiplatelet drug with adenosine diphosphate (ADP) receptor as target spot, the current antiplatelet aggregation being clinically most widely used, antithrombotic reagent/non-thiophene pyridines), such as clopidogrel/prasugrel, and platelet membrane glycoprotein egg IIb/IIIa receptor antagonists are the third generation.As second filial generation thiophene pyridine derivatives, P2Y12-ADP
Receptor antagonist clopidogrel（clopidogrel）There are preferable safety, aspirin and the standard combination that clopidogrel is current Antiplatelet therapy than thiophene chloropyridine, become the goldstandard of antithrombotic reagent treatment.But two medicines are shared causes bleeding event to increase.
Clopidogrel and prasugrel are the higher P2Y12-ADP receptor antagonists of selectivity.ADP is combined with platelet by 3 receptors on platelet membrane in hematoblastic activation：P2X1 receptors, P2Y1 receptors and P2Y12 receptors, play a significant role.P2Y12 receptors belong to a member of GPCR families, after ADP and P2Y12 receptor bindings, two subunits of Gi albumen（α Gi, β γ）Exposure, α Gi subunits are reduced cAMP, cause platelet glycoprotein by suppressing adenyl cyclase
IIb/IIIa is complex activating, and β γ subunits can activate 3 kinases of phosphatidylinositols and be transmitted by a series of Intracellular signals, cause platelet aggregation.P2Y12-ADP receptor antagonists are reduced the binding site of ADP, are reduced platelet aggregation, play antithrombotic effect by competitive or noncompetitive ground and P2Y12 receptor bindings.
The another not enough of clopidogrel is clopidogrel Resistant of increasing concern.Clinically, chlorine resists (Clopidogrel than Gray
Resistance it is) a kind of very universal phenomenon, the incidence rate of this phenomenon is 4% -30%, and in white man, incidence rate is relatively low, in Black African secondly, and in Aisan, chlorine is than incidence rate highest that Gray resists, it is possible to up to 55%.After generation chlorine is than Gray's opposing, the consequence brought is very serious, and cardiovascular event and mortality rate significantly rise.In therapeutic process, the patient of clopidogrel Resistant is easier to thrombosis in acute and subacute stent, and Cardioversion sends out the mortality rate up to 15% -45% of survivor, again myocardial infarction rate up to 60% -70%.
Occur clopidogrel Resistant mechanism it is very complicated, wherein compare for everybody approve mechanism for CytochromeP450 enzymes activity.Research shows, enters blood by gastrointestinal tract first after oral clopidogrel.In blood, 85% clopidogrel is directly metabolized into inactive metabolite by esterase and excretes, wherein only 15% clopidogrel is by CytochromeP450
The metabolism of enzyme institute, the enzyme for participating in this metabolism include CYP3A4, CYP3A5, CYP2C9, CYP1A2, CYP2B6 and CYP2C19, form thiolactone, are then metabolized as the metabolite with anticoagulant active by CYP3A4 enzymes again, and play anticoagulation drug effect.Increasing research shows that the function of CYP450 enzyme systems is weaker in the individual patients liver of generation clopidogrel Resistant or lacks, and so as to cause clopidogrel be metabolized as thiolactone after entering in vivo, is further metabolized as active metabolite and plays drug effect.
For the deficiencies in the prior art, it is an object of the invention to by the structure of modification to clopidogrel and prasugrel, a series of thiophene pyridine derivatives noval chemical compounds are synthesized, after compound is entered in vivo, rapid metabolization is effective metabolite, the metabolism of CYP450 enzyme systems is avoided successfully, reactive compound can be metabolized as directly and play drug effect, so as to solve the problems, such as clopidogrel Resistant.
The content of the invention：
The technical problem to be solved is to overcome above-mentioned weak point, design, synthesizing new thiophene pyridine derivatives, so as to develop the anti-platelet aggregation medicine of good effect, Small side effects.
Specifically, one purpose of the present invention is to provide a kind of thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture.
Further object is that providing the preparation method of the thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture.
A further object of the present invention is to provide with the thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture the pharmaceutical composition as active component.
It is yet a further object of the present invention to provide the purposes of the thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture or pharmaceutical composition in terms of pharmacy.
Further an object is that for the present invention provides the method for being used for therapy-related disease using the thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture or using described pharmaceutical composition.
To achieve these goals, the technical scheme that the present invention takes is as follows：
On the one hand, offer formula of the present invention（I）Shown thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture,
(I)
Wherein：
M is 0 to 2 integer；
R1For hydrogen, halogen, cyano group, alkyl, haloalkyl, hydroxyalkyl, carboxyl or carboxylic acid ester groups；
R2For hydrogen, hydroxyl or C1-C10Alkyl, R4NR5Or C1-C10Alkoxyl, wherein R4、R5For hydrogen or C1-C10Alkyl；
R3For
Or
, wherein R4For C1-C10Non-substituted or X replace straight or branched alkyl, OR6、NR7R8, phenyl, Y replace phenyl, styryl, 4-Vinyl phenol base, 4- hydroxyl -3- methoxyl-styrenes, 3- pyridine radicals, alkenyl or alkynyl；Wherein X is the phenyl that fluorine, chlorine, bromine, iodine, itrile group, nitro, amino, acylamino-, sulfonamido, trifluoromethyl, sulfydryl, hydroxyl, acetoxyl group, methoxyl group, ethyoxyl, carboxyl, methoxy acyl group, ethoxy acyl group, aryloxy group, phenyl or Y replace；Y is fluorine, chlorine, bromine, iodine, itrile group, nitro, amino, acylamino-, sulfonamido, trifluoromethyl, sulfydryl, hydroxyl, acetoxyl group, methoxyl group, ethyoxyl, carboxyl, methoxy acyl group or ethoxy acyl group；R6For C1-C10Straight or branched alkyl or benzyl；R7、R8For C1-C10Straight or branched alkyl；R5For amino acid side groups, the aminoacid is selected from：Lysine, arginine, histidine, ornithine, 2,3- diaminopropionic acids, 2,4- diaminopropionic acids, alanine, L-Valine, leucine, isoleucine, Phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, L-Tyrosine, agedoite, glutamine, aspartic acid, glutamic acid.Described aminoacid can be D types, L-type and DL types.
According to certain embodiments of the present invention, the present invention provides thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture, wherein, the thienopyridine derivative includes following compounds：
Term used herein " pharmaceutical salts " refers to that can retain parent compound is expected physiologically active without producing the salt of any unexpected toxic and side effects, for example：Hydrochlorate, hydrobromate, sulfate, disulfate, phosphate, nitrate, and acetate, oxalates, tartrate, succinate, malate, benzoate, embonate, alginate, mesylate, naphthalene sulfonate, sodium salt, magnesium salt, potassium salt, calcium salt, choline salt, meglumine salt etc..
Described solvated compoundses are hydrate, alcohol adduct etc..
It is technology as well known to those skilled in the art to select and prepare pharmaceutically acceptable salt or solvated compoundses etc..
On the other hand, the present invention also provides above-mentioned thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture, and the preparation method includes making formula（）Shown compound and formula（）、（）The step of shown compound reacts：
Wherein, R1、R2、R3、R4And R5As defined in claim 1；Formula（）Shown compound includes cis-structure and transconfiguration.
Specific embodiment of the invention, the compound of the present invention can be prepared by following manner：
Another further aspect, the present invention also provides the pharmaceutical composition containing thienopyridine analog derivative of the present invention or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture, and which includes the Thienopyridines of the present invention or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture and optional pharmaceutically acceptable carrier of clinical effective dose.The Thienopyridines or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer obtained by the present invention individually or in the form of drug regimen can be administered.Drug regimen of the present invention can be made into various suitable dosage forms according to route of administration.Using one or more physiologically acceptable carrier, comprising excipient and auxiliary agent, they are conducive to reactive compound is processed into the preparation that pharmaceutically can be used.Appropriate dosage form depends on selected route of administration, can be manufactured according to general knowledge well known in the art.
Route of administration can be that oral, non-bowel or local are administered, preferably oral and injection form administration.Can oral drug-delivery preparation include capsule, granule and tablet etc..Patient is swallowed when having any problem, it would however also be possible to employ Sublingual tablet or other non-modes swallowed are administered.The compounds of this invention can be used for being formulated for parenteral or transdermal administration or transmucosal drug delivery.Or be administered by the way of suppository or implants.It will be understood by those skilled in the art that the compounds of this invention can adopt suitable drug delivery system to obtain more favourable effect.
Additionally need and point out, the compounds of this invention using dosage and using method depend on factors, including the subjective judgment of age of patient, body weight, sex, health status, nutriture, the activity intensity of compound, use time, metabolic rate, the order of severity of disease and diagnosis and treatment doctor.Preferred using dosage is between 2～120mg/kg；The dosage of best 24 hours is 20～80mg of per kilogram, and administering mode several times may also be employed.
The present invention is described in further detail with reference to embodiment, it should be understood that the non-scope for being only limitted to these embodiments of the scope of the present invention.
Embodiment 1 ：The synthesis of compound 1
By 11.0g（E）-2-（1-（（S）-1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）In 220ml tetrahydrofurans, Deca 12ml triethylamine adds 3.0g chloroacetic chlorides after stirring 0.5h, 8h is stirred at room temperature, Na is used acetic acid2CO3Solution and salt water washing organic layer, Jing anhydrous Nas2SO4It is dried, is concentrated to dryness.The residue obtains compound 1 by HPLC piece-rate systems（6.3g, 57.3%）, it is white solid.
ESI-MS
m/z：397（M+1）+
Embodiment 2 ：Compound 1,Synthesis
Preparation method reference embodiment 1, by 11.0g（E）-2-（1-（（R）-1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）With 3.0g excess acetyl chlorides, compound 1 is obtained,（5.3g, 48.1%）, it is white solid.
ESI-MS
m/z：397（M+1）+
Embodiment 3 ：Compound 1,Synthesis
Preparation method reference embodiment 1, by 11.0g（E）-2-（1-（1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）With 3.0g excess acetyl chlorides, compound 1 is obtained,（6.0g, 54.5%）, it is white solid.
ESI-MS
m/z：397（M+1）+
Embodiment 4 ：The synthesis of compound 2
By 11.0g（E）-2-（1-（（S）- 2- cyclopropyl -1-（2- fluorophenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）In 220ml tetrahydrofurans, Deca 12ml triethylamine adds 3.6g propionyl chlorides after stirring 0.5h, 8h is stirred at room temperature, Na is used acetic acid2CO3Solution and salt water washing organic layer, Jing anhydrous Nas2SO4It is dried, is concentrated to dryness.The residue obtains compound 2 by HPLC piece-rate systems（5.8g, 52.7%）, it is white solid.
ESI-MS
m/z：405（M+1）+
Embodiment 5 ：Compound 2,Synthesis
Preparation method reference embodiment 4, by 11.0g（E）-2-（1-（（R）- 2- cyclopropyl -1-（2- fluorophenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）Acetic acid and 3.6g propionyl chloride acyl chloride reactions, are obtained compound 2,（6.1g, 55.4%）, it is white solid.
ESI-MS
m/z：405（M+1）+
Embodiment 6 ：Compound 2,Synthesis
Preparation method reference embodiment 4, by 11.0g（E）-2-（1-（2- cyclopropyl -1-（2- fluorophenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）Acetic acid and 3.6g propionyl chloride acyl chloride reactions, are obtained compound 2,（6.0g, 54.5%）, it is white solid.
ESI-MS
m/z：405（M+1）+
Embodiment 7 ：The synthesis of compound 3
By 11.0g（E）-2-（1 -（（S）-2-（Dimethylamino）-1-（2- chlorphenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）In 220ml tetrahydrofurans, Deca 12ml triethylamine adds 6.37g3- methoxy benzoyl chlorides after stirring 0.5h, 8h is stirred at room temperature, Na is used acetic acid2CO3Solution and salt water washing organic layer, Jing anhydrous Nas2SO4It is dried, is concentrated to dryness.The residue obtains compound 3 by HPLC piece-rate systems（6.0g, 54.5%）, it is white solid.
ESI-MS
m/z：502（M+1）+
Embodiment 8 ：Compound 3,Synthesis
Preparation method reference embodiment 7, by 11.0g（E）-2-（1 -（（R）-2-（Dimethylamino）-1-（2- chlorphenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）Acetic acid is reacted with 6.37g 3- methoxy benzoyl chlorides, and compound 3 is obtained,（5.9g, 53.6%）, it is white solid.
ESI-MS
m/z：502（M+1）+
Embodiment 9 ：Compound 3,Synthesis
Preparation method reference embodiment 7, by 11.0g（E）-2-（1 -（2-（Dimethylamino）-1-（2- chlorphenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）Acetic acid is reacted with 6.37g 3- methoxy benzoyl chlorides, and compound 3 is obtained,（5.4g, 49.1%）, it is white solid.
ESI-MS
m/z：502（M+1）+
Embodiment 10 ：The synthesis of compound 4
By 11.0g（E）-2-（1-（（S）-1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）In 220ml tetrahydrofurans, Deca 12ml triethylamine adds 6.0g phenyllacetyl chlorides after stirring 0.5h, 8h is stirred at room temperature, Na is used acetic acid2CO3Solution and salt water washing organic layer, Jing anhydrous Nas2SO4It is dried, is concentrated to dryness.The residue obtains compound 4 by HPLC piece-rate systems（5.6g, 50.9%）, it is white solid.
ESI-MS
m/z：473（M+1）+
Embodiment 11 ：Compound 4,Synthesis
Preparation method reference embodiment 10, by 11.0g（E）-2-（1-（（S）-1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）Acetic acid is reacted with 6.0g phenyllacetyl chlorides, and compound 4 is obtained,（5.3g, 48.2%）, it is white solid.
ESI-MS
m/z：473（M+1）+
Embodiment 12 ：Compound 4,Synthesis
Preparation method reference embodiment 10, by 11.0g（E）-2-（1-（1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）Acetic acid is reacted with 6.0g phenyllacetyl chlorides, and compound 4 is obtained,（5.7g, 51.8%）, it is white solid.
ESI-MS
m/z：473（M+1）+
Embodiment 13 ：The synthesis of compound 5
By 11.0g（E）-2-（1-（（S）-1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）In 220ml tetrahydrofurans, Deca 12ml triethylamine adds 3.0g chloroacetic chlorides after stirring 0.5h, 8h is stirred at room temperature, Na is used acetic acid2CO3Solution and salt water washing organic layer, Jing anhydrous Nas2SO4It is dried, is concentrated to dryness.The residue obtains product 7.4g by HPLC piece-rate systems；Product is dissolved in into 30mlCH2Cl2In, Deca H2O2（2.3ml, 17mmol）, the mixture is then stirred at room temperature 4 hours, reaction is quenched with water.Use Na2CO3Solution and salt water washing organic layer, Jing anhydrous Nas2SO4It is dried, is concentrated to dryness.The residue obtains compound 5 by HPLC piece-rate systems（5.6g, 50.9%）, it is white solid.
ESI-MS
m/z：413（M+1）+
Embodiment 14 ：Compound 5,Synthesis
Preparation method reference embodiment 13, by 11.0g（E）-2-（1-（（R）-1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）Acetic acid and 3.0g excess acetyl chlorides obtain product again with 2.3mlH2O2Reaction, is obtained compound 5,（5.9g, 53.6%）, it is white solid.
ESI-MS
m/z：413（M+1）+
Embodiment 15 ：Compound 5,Synthesis
Preparation method reference embodiment 13, by 11.0g（E）-2-（1-（1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）Acetic acid and 3.0g excess acetyl chlorides obtain product again with 2.3mlH2O2Reaction, is obtained compound 5,（6.0g, 54.5%）, it is white solid.
ESI-MS
m/z：413（M+1）+
Embodiment 16 ：The synthesis of compound 6
By 11.0g（E）-2-（1 -（（S）-2-（Dimethylamino）-1-（2- chlorphenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）In 220ml tetrahydrofurans, Deca 12ml triethylamine adds 6.37g3- methoxy benzoyl chlorides after stirring 0.5h, 8h is stirred at room temperature, Na is used acetic acid2CO3Solution and salt water washing organic layer, Jing anhydrous Nas2SO4It is dried, is concentrated to dryness.The residue obtains product 7.4g by HPLC piece-rate systems；Product is dissolved in into 30mlCH2Cl2In, Deca 6.0mlH2O2, the mixture is then stirred at room temperature 4 hours, reaction is quenched with water.Use Na2CO3Solution and salt water washing organic layer, Jing anhydrous Nas2SO4It is dried, is concentrated to dryness.The residue obtains compound 6 by HPLC piece-rate systems（5.6g, 50.9%）, it is white solid.
ESI-MS
m/z：548（M+1）+
Embodiment 17 ：Compound 6,Synthesis
Preparation method reference embodiment 13, by 11.0g（E）-2-（1 -（（R）-2-（Dimethylamino）-1-（2- chlorphenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）The reaction of acetic acid and 6.37g3- methoxy benzoyl chlorides obtain product again with 6.0mlH2O2Reaction, is obtained compound 6,（6.0g, 54.5%）, it is white solid.
ESI-MS
m/z：548（M+1）+
Embodiment 18 ：Compound 6,Synthesis
Preparation method reference embodiment 13, by 11.0g（E）-2-（1 -（2-（Dimethylamino）-1-（2- chlorphenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）The reaction of acetic acid and 6.37g3- methoxy benzoyl chlorides obtain product again with 6.0mlH2O2Reaction, is obtained compound 6,（, 5.6g, 51.0%）, it is white solid.
ESI-MS
m/z：548（M+1）+
Embodiment 19 ：The synthesis of compound 7
Under water bath condition, N-epsilon- tertbutyloxycarbonyls -1B 7.6g, N, N '-dicyclohexylcarbodiimide 0.91g, 4- dimethylamino pyridine 0.3g, with anhydrous methylene chloride 30ml stirring and dissolving.It is subsequently added（E）-2-（1-（（S）-1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）Acetic acid 9.0g, stirring at normal temperature is overnight.Solids removed by filtration insoluble matter, filtrate solvent evaporated；Add diethyl ether in residue, the insoluble impurity being filtered to remove in solution.Filtrate concentrates, and crosses post as developing solvent is quick with ether, collects product frac.Concentrating under reduced pressure obtains product 2.7g；7 yield 30.0% of compound.
ESI-MS
m/z：484（M+1）+
Embodiment 20 ：Compound 7,Synthesis
Preparation method, will with reference to embodiment 19（E）-2-（1-（（R）-1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）Acetic acid and N-epsilon- tertbutyloxycarbonyls -1B reaction.Obtain compound I-7,。
ESI-MS
m/z：484（M+1）+
Embodiment 21 ：Compound 7,Synthesis
Preparation method, will with reference to embodiment 19（E）-2-（1-（（R）-1-（2- chlorphenyls）- 2- methoxyl group -2- oxoethyl -4- sulfhydryl piperidine -3- subunits）Acetic acid and N-epsilon- tertbutyloxycarbonyls-D-Lys reaction.Obtain compound I-7,。
ESI-MS
m/z：484（M+1）+
Embodiment 22 ：The synthesis of compound 8
Under water bath condition, N- tertbutyloxycarbonyls-L-Arginine 9.3g, N, N '-dicyclohexylcarbodiimide 0.91g, 4- dimethylamino pyridine 0.3g, with anhydrous methylene chloride 30ml stirring and dissolving.It is subsequently added（E）-2-（1-（（S）- 2- cyclopropyl -1-（2- fluorophenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）Acetic acid 9.0g, stirring at normal temperature is overnight.Solids removed by filtration insoluble matter, filtrate solvent evaporated；The residue obtains product 3.4g by HPLC piece-rate systems；Product is dissolved in 40 dichloromethane, Deca 3.4ml hydrogen peroxide, compound 4h is so stirred at room temperature, reaction is quenched with water.Use Na2CO3Solution and salt water washing organic layer, Jing anhydrous Nas2SO4It is dried, is concentrated to dryness.The residue obtains compound 81.3g by HPLC piece-rate systems, and 38.2%.
ESI-MS
m/z：521（M+1）+
Embodiment 23 ：Compound 8,Synthesis
Preparation method, will with reference to embodiment 22（E）-2-（1-（（R) -2- cyclopropyl -1-（2- fluorophenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）Acetic acid and N- tertbutyloxycarbonyls-D-Arg reaction.Obtain compound I-8,。
ESI-MS
m/z：521（M+1）+
Embodiment 24 ：Compound 8,Synthesis
Preparation method, will with reference to embodiment 22（E）-2-（1-（- 2- cyclopropyl -1-（2- fluorophenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）Acetic acid is reacted with N- tertbutyloxycarbonyl-DL- arginine.Obtain compound I-8,。
ESI-MS
m/z：521（M+1）+
Embodiment 25 ：The synthesis of compound 9
Under water bath condition, tertbutyloxycarbonyl-L-Orn 7.9g, N, N '-dicyclohexylcarbodiimide 0.91g, 4- dimethylamino pyridine 0.3g, with anhydrous methylene chloride 30ml stirring and dissolving.It is subsequently added（E）-2-（1 -（（S）-2-（Dimethylamino）-1-（2- chlorphenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）Acetic acid 9.0g, stirring at normal temperature is overnight.Solids removed by filtration insoluble matter, filtrate solvent evaporated；The residue obtains product 3.5g by HPLC piece-rate systems；Product is dissolved in 40ml dichloromethane, Deca 8ml hydrogen peroxide, compound 4h is so stirred at room temperature, reaction is quenched with water.Use Na2CO3Solution and salt water washing organic layer, Jing anhydrous Nas2SO4It is dried, is concentrated to dryness.The residue obtains 9 1.0g of compound by HPLC piece-rate systems, and 28.6%.
ESI-MS
m/z：514（M+1）+
Embodiment 26 ：Compound 9,Synthesis
Preparation method, will with reference to embodiment 25（E）-2-（1 -（（S）-2-（Dimethylamino）-1-（2- chlorphenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）Acetic acid and tertbutyloxycarbonyl-D-Orn reaction.Obtain compound I-9,。
ESI-MS
m/z：514（M+1）+
Embodiment 27 ：Compound 9,Synthesis
Preparation method, will with reference to embodiment 25（E）-2-（1 -（（S）-2-（Dimethylamino）-1-（2- chlorphenyls）- 2- oxoethyls）- 4- sulfhydryl piperidine -3- subunits）Acetic acid is reacted with tertbutyloxycarbonyl-DL- ornithines.Obtain compound I-9,。
ESI-MS
m/z：514（M+1）+
Embodiment 28 ：Platelet aggregation inhibitory activity is tested
Medicine and preparation：Positive drug is clopidogrel sulfate.Positive drug and test-compound（It is prepared by above-described embodiment）Suspension is made into for animal administrable with 0.5%CMC-Na (sodium carboxymethyl cellulose).
Animal：Wistar rats, 200-250g, male, Jiangning county Qinglongshan animal reproduction field.
Instrument：Platelet aggregation instrument (560Ca), CHRONO-LOG, the U.S.
Method：With reference to BORN turbidimetrys (Nature, 1962,194 (4832)：927) pharmacological activity test of antiplatelet aggregation, is carried out to the compounds of this invention (above-described embodiment preparation).To rich in addition coagulant polymers adenosine diphosphate (ADP) in hematoblastic blood plasma (PRP)
(ADP) stir, make platelet aggregation.It is hematoblastic to assemble the change for causing optical density, can be detected by spectrophotometer.This experiment can be evaluated test-compound and the platelet aggregation for causing is administered in vivo or in vitro.
Platelet aggregation inhibitory activity is tested：Rat is grouped at random, gastric infusion test-compound (is suspended using 0.5% carboxymethyl cellulose is front used), and dosage is 3mg/kg, and the oral gavage of blank control group gives the 0.5% of same volume
CMC-Na.After 2h, abdominal aortic blood (pentobarbital sodium intraperitoneal injection of anesthesia), 3.8% sodium citrate anticoagulant, whole blood are that 9: 1,1000rpm is centrifuged 7min with the ratio of anticoagulant, prepare platelet rich plasma (PRP).PRP is adjusted with platelet poor plasma (PPP), makes platelet count be maintained at 2 × 106/ml.Take in PRP addition test cups, 37 DEG C of incubation 10min are returned to zero with PRP, PPP adjusts 100%, with ADP (final concentration of 5 μM) as derivant, platelet aggregation percent is determined with platelet aggregation instrument by turbidimetry, statistics comparison is carried out with t- inspections.Platelet aggregation inhibition rate is calculated as follows：
Platelet aggregation inhibition rate (%)=[1- (delivery tube aggregation percentage rate/control tube aggregation percentage rate)] × 100%.
As a result following table shows that the platelet aggregation inhibition rate after turbidimetry measures Oral Administration in Rats test-compound, part of test results are as shown in the table.As a result show, most of test-compound shows the platelet aggregation inhibitory activity more higher than clopidogrel, also, (S)-configuration of compound（Such as compound 1, embodiment 1）Than its corresponding (R)-configuration enantiomers（Such as compound 1 ', embodiment 2）With raceme mixture (such as compound 1 ", 3) embodiment all show higher suppression platelet aggregation.
| Medicine | Dosage（mg/Kg) | Size of animal | Maximum agglutination rate |
| Blank | - | 6 | - |
| Clopidogrel sulfate | 5 | 6 | 31.6 |
| 1 (embodiment 1 of compound） | 5 | 6 | 61.5 |
| Compound 1,(embodiment 2） | 5 | 6 | 23.4 |
| Compound 1,(embodiment 3） | 5 | 6 | 18.4 |
| 2 (embodiment 4 of compound） | 5 | 6 | 48.3 |
| Compound 2,(embodiment 5） | 5 | 6 | 19.7 |
| Compound 2,(embodiment 6） | 5 | 6 | 11.7 |
| 3 (embodiment 7 of compound） | 5 | 6 | 53.8 |
| Compound 3,(embodiment 8） | 5 | 6 | 26.8 |
| Compound 3,(embodiment 9） | 5 | 6 | 14.6 |
| 4 (embodiment 10 of compound） | 5 | 6 | 46.4 |
| Compound 4,(embodiment 11） | 5 | 6 | 19.5 |
| Compound 4,(embodiment 12） | 5 | 6 | 13.9 |
| 5 (embodiment 13 of compound） | 5 | 6 | 43.2 |
| Compound 5,(embodiment 14） | 5 | 6 | 21.6 |
| Compound 5,(embodiment 15） | 5 | 6 | 19.6 |
| 6 (embodiment 16 of compound） | 5 | 6 | 59.8 |
| Compound 6,(embodiment 17） | 5 | 6 | 21.7 |
| Compound 6,(embodiment 18） | 5 | 6 | 15.2 |
| 7 (embodiment 19 of compound） | 5 | 6 | 58.8 |
| Compound 7,(embodiment 20） | 5 | 6 | 25.3 |
| Compound 7,(embodiment 21） | 5 | 6 | 10.4 |
| 8 (embodiment 22 of compound） | 5 | 6 | 49.3 |
| Compound 8,(embodiment 23） | 5 | 6 | 18.7 |
| Compound 8,(embodiment 24） | 5 | 6 | 10.6 |
| 9 (embodiment 25 of compound） | 5 | 6 | 59.8 |
| Compound 9,(embodiment 26） | 5 | 6 | 18.7 |
| Compound 9,(embodiment 27） | 5 | 6 | 10.2 |
Claims (8)
1. the thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture shown in formula (I),
(I)
Wherein：
M is 0 to 2 integer；
R1For hydrogen, halogen, cyano group, alkyl, haloalkyl, hydroxyalkyl, carboxyl or carboxylic acid ester groups；
R2For hydrogen, hydroxyl or C1-C10Alkyl, R4NR5Or C1-C10Alkoxyl, wherein R4、R5For hydrogen or C1-C10Alkyl；
R3ForOr
, wherein R4For C1-C10Non-substituted or X replace straight or branched alkyl, OR6、NR7R8, phenyl, Y replace phenyl, styryl, 4-Vinyl phenol base, 4- hydroxyl -3- methoxyl-styrenes, 3- pyridine radicals, alkenyl or alkynyl；Wherein X is the phenyl that fluorine, chlorine, bromine, iodine, itrile group, nitro, amino, acylamino-, sulfonamido, trifluoromethyl, sulfydryl, hydroxyl, acetoxyl group, methoxyl group, ethyoxyl, carboxyl, methoxy acyl group, ethoxy acyl group, aryloxy group, phenyl or Y replace；Y is fluorine, chlorine, bromine, iodine, itrile group, nitro, amino, acylamino-, sulfonamido, trifluoromethyl, sulfydryl, hydroxyl, acetoxyl group, methoxyl group, ethyoxyl, carboxyl, methoxy acyl group or ethoxy acyl group；R6For C1-C10Straight or branched alkyl or benzyl；R7、R8For C1-C10Straight or branched alkyl；R5For amino acid side groups, the aminoacid is selected from：Lysine, arginine, histidine, ornithine, 2,3- diaminopropionic acids, 2,4- diaminopropionic acids, alanine, L-Valine, leucine, isoleucine, Phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, L-Tyrosine, agedoite, glutamine, aspartic acid, glutamic acid.
2. aminoacid according to claim 1 can be D types, L-type and DL types.
3. thienopyridine analog derivative according to claim 1 or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture, it is characterised in that the derivant includes following compounds：
.。
4. the preparation method of the thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture any one of a kind of claim 1 to 2, the preparation method include making formula () shown in compound and formula ()、() shown in compound the step of react：
Wherein, R1、R2、R3、R4And R5As defined in claim 1；Formula（）Shown compound includes cis-structure and transconfiguration.
5. the pharmaceutical composition containing thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture described in claim 1.
6. pharmaceutical composition according to claim 5, it is characterised in that wherein containing one or more pharmaceutically acceptable carriers.
7. the thienopyridine analog derivative or its pharmaceutical salts, solvated compoundses, polymorphs body, enantiomer or racemic mixture according to any one of claim 1,3,4 or the purposes according to the pharmaceutical composition described in claim 5 to 6 in the medicine for preparing thrombosis and thromboembolism relevant disease.
8. pharmaceutical composition according to claim 7, the thrombosiss postoperative for preventing or treating atheromatosiss, myocardial infarction, apoplexy, ischemic cerebral thrombosiss, peripheral arterial disease, acute coronary syndrome or calcification score.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848497A (en) * | 2020-07-28 | 2020-10-30 | 内蒙古医科大学 | Clopidogrel active metabolite derivative, prodrug thereof, preparation method and application thereof |
| WO2022022559A1 (en) * | 2020-07-29 | 2022-02-03 | Shanghai Curegene Pharmaceutical Co., Ltd. | Antiplatelet drugs and uses thereof |
| WO2023144782A1 (en) * | 2022-01-28 | 2023-08-03 | 上海柯君医药科技有限公司 | Pharmaceutical composition of antiplatelet drug, and use thereof |
| US11834413B2 (en) | 2020-07-29 | 2023-12-05 | Shanghai Curegene Pharmaceutical Co Ltd. | Antiplatelet drugs and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1192019C (en) * | 1996-08-28 | 2005-03-09 | 三共株式会社 | Cyclic amine derivatives |
| JP3907029B2 (en) * | 1998-02-27 | 2007-04-18 | 三共株式会社 | Pharmaceutical containing cyclic amine derivative |
-
2015
- 2015-09-25 CN CN201510621912.5A patent/CN106554303A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1192019C (en) * | 1996-08-28 | 2005-03-09 | 三共株式会社 | Cyclic amine derivatives |
| JP3907029B2 (en) * | 1998-02-27 | 2007-04-18 | 三共株式会社 | Pharmaceutical containing cyclic amine derivative |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848497A (en) * | 2020-07-28 | 2020-10-30 | 内蒙古医科大学 | Clopidogrel active metabolite derivative, prodrug thereof, preparation method and application thereof |
| WO2022022559A1 (en) * | 2020-07-29 | 2022-02-03 | Shanghai Curegene Pharmaceutical Co., Ltd. | Antiplatelet drugs and uses thereof |
| US11834413B2 (en) | 2020-07-29 | 2023-12-05 | Shanghai Curegene Pharmaceutical Co Ltd. | Antiplatelet drugs and uses thereof |
| WO2023144782A1 (en) * | 2022-01-28 | 2023-08-03 | 上海柯君医药科技有限公司 | Pharmaceutical composition of antiplatelet drug, and use thereof |
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